Department of Biochemical Engineering, Banaras Hindu university, UP, India.
Mycobacterium tuberculosis a causative agent of tuberculosis is gram-positive and slow growing bacterium. Decaprenyl-phosphoryl-β-D-ribose oxidase is an important enzyme involved in the cell wall synthesis of Mycobacterium tuberculosis. It is involved in the epimerization of decaprenyl-phosphoryl-D-ribose into decaprenyl-phosphoryl-D-arabinose, a precursor for arabinan synthesis. Its 3-D structure has not yet been reported either by X-ray crystallography or NMR. Therefore, model of decaprenyl-phosphoryl-β-D-ribose oxidase was determined by homology modeling, using multi-template approach based on crystal structure of 2EXR.pdb and 2Q4W.pdb with score=48.9 bits and identities=42/148 (29%). The computed model was subjected to refinement on the basis of consensus generated from 2D structure. The energy minimization and molecular dynamics simulation was performed by DESMOND using OPLS-AA force field and finally evaluated using SAVES server to obtain reliable structure. The modeled protein was used for structure-based virtual screening against ZINC database through molecular docking using Molegro Virtual Docker (MVD) 4.2.0. Out of 19365 ZINC database molecules, top 10 docked complexes obtained after virtual screening were enumerated and validated based on Molegro Virtual Docker 4.2.0 Scoring function and ADME properties. On the basis of docking energies top 10 ligands were selected for validation using AutoDock/Vina scoring function to compare their results. Thus the complex scoring, docking energies and binding affinities revealed that these ligand molecules could be promising inhibitors for decaprenyl-phosphoryl-beta-D-ribose-2′-oxidase. The docking studies also reveal that Tyr (335), Thr (426) are prominently involved in hydrogen bond interactions with the ligands and thus they are important determinant residues in binding with ligands. Read more…